Transcriptomic impact of IMA-08401, a novel AHR-agonist resembling laquinimod, on rat liver
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PROVIDER: PRJNA521341 | ENA |
REPOSITORIES: ENA
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Project description:IMA-08401 (C2) represents a novel AHR agonist and selective AHR modulator (SAHRM) that is structurally similar to laquinimod (LAQ). Although both compounds produce an identical AHR-active metabolite, IMA-06201 (DELAQ) in vivo, C2 generates it to a far greater degree. SAHRMs have been proposed as therapeutic options for autoimmune disorders, including multiple sclerosis. So far, clinical trials on LAQ have not reported any significant toxic outcomes and C2 has shown low toxicity in rats; however, more research is required due to the functional resemblance of these compounds to the highly toxic AHR agonist, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Here, we report transcriptomic profiling of rat liver following acute (single-dose) and sub-acute exposure (repeated dosing for 5 days followed by a 5-day recovery period) to high doses of C2. Exposure to C2 leads to activation of the AHR, as shown by changes in mRNA abundance of the prototypical AHR-response gene Cyp1a1. We identify a heightened response early after exposure (1 day) that drops off considerably by day 10. Acute exposure to C2 produces a significant immune response, with a focus on antiviral and antibacterial responses that highlights the dual effects of AhR agonists as immunomodulators. Sub-acute exposure leads to an increase in oxidative stress in the liver, the consequences of which require further study on sensitive tissues, such as the CNS and immune system which may be compromised in patients with the target autoimmune disorders.
2019-03-26 | GSE126216 | GEO
Project description:IMA-08401 (C2) is a novel aryl hydrocarbon receptor (AHR) agonist and selective AHR modulator (SAHRM) that is structurally similar to laquinimod (LAQ). Both compounds are converted to the AHR-active metabolite DELAQ (IMA-06201) in vivo. SAHRMs have been proposed as therapeutic options for various autoimmune disorders. Clinical trials on LAQ have not reported any significant toxic outcomes and C2 has shown low toxicity in rats; however, their functional resemblance to the highly toxic AHR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) raises questions. Here, we characterize the hepatic transcriptomic changes induced by acute (single-dose) and subacute exposure (repeated dosing for 5 days followed by a 5-day recovery period) to C2 in Sprague-Dawley rats. Exposure to C2 leads to activation of the AHR, as shown by altered transcription of Cyp1a1. We identify a heightened response early after exposure that drops off by day 10. Acute exposure to C2 leads to changes to transcription of genes involved in antiviral and antibacterial responses, which highlights the immunomodulator effects of this AHR agonist. Subacute exposure causes an oxidative stress response in the liver, the consequences of which require further study on target tissues such as the CNS and immune system, both of which may be compromised in this patient population.
| S-EPMC6471016 | biostudies-literature
Project description:Expression analysis of colonic neurons stimulated with AhR agonist (3-methylcholanthrene)
| PRJNA589101 | ENA
Project description:Neural control of visceral organ function is essential for homeostasis and health. Intestinal peristalsis is critical for digestive physiology and host defence and is often dysregulated in gastrointestinal (GI) disorders. Luminal factors, such as diet and microbiota regulate neurogenic programs of gut motility, but the underlying molecular mechanisms remain unclear. Here we show that the transcription factor Aryl hydrocarbon Receptor (AhR) functions as a biosensor in intestinal neural circuits linking their functional output to the microbial environment of the gut lumen. Using nuclear RNA sequencing of mouse enteric neurons representing distinct intestinal segments and microbiota states, we demonstrate that the intrinsic neural networks of the colon exhibit unique transcriptional profiles controlled by the combined effects of host genetic programmes and microbial colonisation. Microbiota-induced expression of AhR in neurons of the distal gastrointestinal tract enables them to respond to the luminal environment and induce expression of neuron-specific effector mechanisms. Neuron-specific deletion of Ahr or constitutive overexpression of its negative feedback regulator CYP1A1, results in reduced peristaltic activity of the colon, similar to that observed in microbiota-depleted mice. Finally, expression of Ahr in enteric neurons of antibiotic-treated mice partially restores intestinal motility. Taken together, our experiments identify AhR signalling in enteric neurons as a regulatory node that integrates the luminal environment with the physiological output of intestinal neural circuits towards gut homeostasis and health. The enteric nervous system (ENS) encompasses the intrinsic neural networks of the gastrointestinal (GI) tract, which regulate most aspects of intestinal physiology, including peristalsis. In addition to host-specific genetic programmes, microbiota and diet have emerged as critical regulators of gut tissue physiology and changes in the microbial composition of the lumen often accompany GI disorders. We found that gut environmental sensor Aryl hydrocarbon receptor (AhR) is induced in colonic neurons in response to microbiota colonisation and regulates intestinal peristalsis in an AhR ligand-dependent manner. In this experiment, we used RNA sequencing to identify genes regulated in mouse colonic neurons by AhR activation.
2019-11-13 | GSE140292 | GEO
Project description:ChIP-seq was done on one lymphoblastoid cell lines for vehicle control, or 3-MC agonist treatment to identify AHR binding regions throughout the genome. We identified 17,688 common binding peaks between all ChIP treatments
2018-07-06 | GSE116632 | GEO
Project description:Allergen-specific immunotherapy (AIT) is able to restore immune tolerance to allergens in allergic patients. However, some patients do not or only poorly respond to current treatment protocols. Therefore, there is a need for deeper mechanistic insights and further improvement of treatment strategies. AIT was combined with the application of the high-affinity AhR agonist 10-chloro-7H-benzimidazo[2,1-a]benzo[de]iso-quinolin-7-one (10-Cl-BBQ) as an adjuvant to investigate the effects of AhR activation on therapeutic outcome in a murine model of OVA-induced AAI. To assess differences in Th cell populations CD4+ T cells from the lung tissue were enriched and subjected to sc-RNAseq analysis.
2024-05-06 | E-MTAB-14030 | biostudies-arrayexpress
Project description:RNA-seq was done on eight different lymphoblastoid cell lines for vehicle control, 3-MC agonist treatment and GNF-351 antagonist treatment for AHR to look at AHR regulated genes with different genetic backgrounds. We identified 69 genes that were highly differentially expressed after 3-MC or GNF-351 antagonist treatment with variation in the degree fo differential expression between the eight cell lines.
2018-07-06 | GSE116637 | GEO
Project description:ChIP-seq was done on cryopreserved primary human hepatocyte with vehicle control - 0.1% dimethylsulfide (DMSO), or 1nM 2,3,7,8 tetrachlorodibezno-p-dioxin (TCDD) agonist treatment to identify AHR binding regions throughout the genome. We identified 1,984 binding peaks when comparing TCDD vs. vehicle control
2022-06-09 | GSE205502 | GEO
Project description:(Abstract) Toxicogenomics has great potential for enhancing our understanding of environmental chemical toxicity, hopefully leading to better-informed human health risk assessments. This study employed toxicogenomic technology to reveal species differences in response to two prototypical aryl hydrocarbon receptor (AHR) agonists, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and the polychlorinated biphenyl (PCB) congener PCB 126. Dose responses of primary cultures of rat and human hepatocytes were determined using species-specific microarrays sharing over 4,000 gene orthologs. Forty-seven human and 79 rat genes satisfied dose response criteria for both chemicals and were subjected to further analysis including the calculation of EC50 and the relative potency (REP) of PCB 126 for each gene. Only 5 responsive orthologous genes were shared between the two species, yet the geometric mean of the REPs for all rat and human modeled responsive genes were 0.06 (95% Confidence Interval (CI); 0.03-0.1) and 0.002 (95% CI; 0.001-0.005), respectively, suggesting broad species differences in the initial events that follow AHR activation but precede toxicity. This indicates that there are species differences in both the specific genes that responded and the agonist potency and relative potency for those genes. This observed insensitivity of human cells to PCB 126 is consistent with more traditional measurements of AHR activation (i.e., CYP1A1 enzyme activity) and suggests that the species difference in PCB 126 sensitivity is likely due to certain aspects of AHR function. That a species divergence also exists in this expanded AHR-regulated gene repertoire is a novel finding and should help when extrapolating animal data to humans.
2009-08-19 | GSE14554 | GEO